Intratumoral BO-112, a double-stranded RNA (dsRNA), alone and in combination with systemic anti-PD-1 in solid tumors

Background: BO-112 is a dsRNA (poly I:C) formulated with the cationic carrier polyethylenimine, which improves its intracellular delivery. Preclinically it acts by activating TLR3, RIG-1 and MDA-5, leading to an immunogenic cell death and increasing immune-checkpoint inhibition effects. Intratumoral (IT) BO-112 alone or combined with systemic anti PD-1 is being analyzed in this first in human clinical trial (NCT02828098). Methods: 28 patients (pts) with solid tumors and metastases >1 cm amenable to IT injection were divided in 4 cohorts (C). C1: single IT BO-112 dose of 0.6 mg (N = 6); C2: 1mg IT BO-112 qw x 2-3 doses (N = 7). C3: 0.6 mg IT BO-112 qw x 2-3 doses (N = 3); C4: Pts with primary refractory tumors to anti PD-1 were treated with 1mg IT BO112 qw x 2 or 3 doses before continuing nivolumab or pembrolizumab combined with BO-112, until progression, limiting toxicity or up to 1y (N = 12). Pre & post treatment biopsies from the injected lesion were analysed for necrosis, apoptosis, immune infiltrate and gene expression profiles. PK, cytokines and circulating immune cells were studied in pre and post BO-112 blood samples. In C4, response by RECIST 1.1 was assessed. Results: Main G3-5 AEs, biological effects of C1-3 and safety from C4 are summarized in the table. No safety warnings were detected with the combination. BO-112 was not detected in blood. In C4 (combination cohort) disease control rate at 1st assessment (9-10 weeks) was 7/12 (58%) and objective response rate 2/12 (17%), one in melanoma and one in renal cancer. Conclusions: IT BO-112 has demonstrated a manageable safety profile alone and combined with anti PD-1. Its mechanism of action comprises direct antitumor effect, innate and adaptive immune system activation. Combination with anti PD-1 is feasible in anti PD-1 refractory pts. Preliminary efficacy analysis suggests the potential to halt or reverse primary resistance to anti-PD1 treatment. This cohort is being expanded to include up to 30 pts. Clinical trial identification: NCT02828098. Legal entity responsible for the study: Bioncotech Therapeutics S.L. Funding: Bioncotech Therapeutics S.L. Disclosure: I. Marquez Rodas: Advisory role, honoraria, travel grant: BMS, MSD, Roche, Novartis, Pierre Fabre, Amgen, Merck, Bioncotech. A. Calles: Honoraria, consulting fees: AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Novartis, Merck Sharp & Dohme, Bristol-Myers Squibb. S. Lopez-Tarruella: Advisory role, honoraria, travel grants: Roche, Novartis, Celgene, Pfizer, AstraZeneca. P.P. Lopez-Casas: Employee of Bioncotech Therapeutics. D. Tersago: Employee of Bioncotech Therapeutics S.L.; Consulting fees: Convert Pharmaceuticals S.A. M. Quintero: CEO of Bioncotech Therapeutics S.L. S. Martin-Algarra: Advisory role: BMS, MSD, Novartis, Roche, Amgen. M. Martín: Advisory role or speaker honoraria: AstraZeneca, Novartis, Roche-Genentech, Pfizer, GSK, Pharmamar, Taiho Oncology, Lilly; Grants: Novartis, Roche. I. Melero: Consultant: Bristol-Myers Squibb, Roche-Genentech, Bayer, Alligator, Tusk, Bioncotech, Medimmune, Genmab, F-Star; Commercial grants: Bristol Myers Squibb, Roche-Genentech, Alligator. All other authors have declared no conflicts of interest.Table: LBA39COHORTG3-5 AEs N (%)G3-5 related AEs N (%)Necrosis or apoptosis (% evaluable)Increase (Δ) in immune gene expression (% evaluable)Δ circulating immune cells (%)BO-112 Monotherapy6 (38)2 (13)10/13 (77)6/13 (46)14/16 (88)Combination BO-112+anti PD-18 (67)0 (0)NA Open table in a new tab